(1-indolinyl)-lower alkylamidoximes and -amidine



United States Patent ABSTRACT OF THE DISCLOSURE Newindolinyl-lower-alkylamidoximes, -amidines, and -guanidines useful ashypotensive agents, tranqui izers, and sedatives.

This application is a continuation-in-part of my prior copendingapplication Ser. No. 519,458, filed Jan. 10, 1966, now U.S. Patent3,478,039, patented Nov. 11, 1969, which in turn. is acontinuation-in-part of my prior copending application Ser. No. 345,846,filed Feb. 19, 1964, now U .8. Patent 3,354,174, patented Nov. 21, 1967.

This invention relates to the field of amidoximes, amidines, andguanidines, their acid-addition salts, and to intermediates andprocesses therefor.

The compounds of the invention are represented by the general formulas:

Y'CN

wherein Ar is a bicyclic aromatic nitrogen heterocyclie radical havingfused five and six membered rings and containing from two to three ringnitrogen atoms which can be in any position of the two rings; indolyl(in the compounds of Formula Ia only); indolinyl; pyrrolyl; pyrazolyl;imidazolyl; phenothiazinyl; 10,11-dihydro-5H dibenz[b,f]azepinyl;dibenzo [a,d] [1,4] cyclohept'adienylidenyl; or1,2,3,4-tetrahydrocarbazolyl (in any of which values for Ar, the Y or'Y'group can be attached to any non-bridging ring carbon or nitrogen atomof the Ar moiety); R is hydrogen, lower-alkyl, lower-alkanoyl, orhydroxy; R is hydrogen or lower-alkyl; R is hydrogen, lower alkanoyl, orlower-alkyl; Y, in the compounds of Formulas Ia or Ib, is a singlechemical bond or alkylene containing from one to five carbon atoms; Y isalkylene containing from one to six carbon atoms; and n is one of theintegers 1 and 2. Moreover, when Y and Y are alkylene, they can also besubstituted on any of the carbonatoms thereof by a hydroxy group. Themore convenient synthetic methods are based on use of an aldehydecyanohydrin of the nitrile, Ar Y'CN, in the general procedures describedherein, and these methods afford those compounds where the hydroxy groupis attached-to the carbon atom adjacent to the amidoxime group (FormulaIa) or the amidine group (Formula 111), and such compounds arepreferred. 1

In the above'Formulas Ia, b, and 0, R R and R besides representinglower-alkyl, can also repres nt groups such as lower-alkenyl e.g.1-(2-propenyl), 1-(2 methyI-Z-propenyl), and the like; lower-alkynyl,e.g. 1- (2-propynyl), 1-(2-butynyl); or benzyl. Moreover, in thecompounds of Formulas Ib and 10, the groups R on the terminal nitrogenatom can be the same or different or 3,501,497 Patented Mar. 17, 1 9 70canbe joined together either through an alkylene chain or an alkylenechain interrupted by a hetero atom to form,

with the nitrogen atom to which they are attached, a

heterocyclic ring such as pyrrolidine, piperidine, morpholine,thiomorpholine, and the like. I

Furthermore, the groups R and R besides representing' lower-alkanoyl canalso represent groups such as benzoyl.

When Ar represents a bicyclic aromatic nitrogen hetero-' cyclic radicalhaving fused five and six membered rings and containing from two tothree ring nitrogen atoms which can be in any position of the two rings,it is preferably of the 4.3.0 bridged system and is attached to Y (or Y)through an atom of the five membered ring. An especially preferred groupof said heterocyclic bicyclic I radicals includes 1- and3-(2-azaindolyl); 1-, 2-, and 3-(4- azaindolyl); 1-, 2-, and3-(5-azaindolyl); 1-, 2-, and 3-(6- imidazolyl; 1 l-H-benzotriazolyl) 2-(Z-H-benzotriazo lyl); and 3-(pyrido-[2, 1-c]-s-triazolyl).

The compounds of Formula Ia where Y' is a hydroxyalkylene group havingthe hydroxy group attached to the carbon atom adjacent to the amidoximegroup have the l H NOR3 Rz where R R R Ar, and n have the meanings givenabove, and Y" is C H here In is an integer from 0 to 4. In the abovegeneral Formulas Ia, Ib, and I0, when R, R or R represent lower-alkylthe lower-alkyl moiety can be straight or branched and can contain fromone to about four carbon atoms. Thus R R and R represent, inter aliamethyl ethyl isopropyl or n-butyl.

In the above general Formula Ia, when R and R are lower-alkanoyl, theycan be straight or branched and can contain from one to about fourcarbon atoms. Thus R and R represent, inter alia, formyl, acetyl,propionyl, or isobutyryl.

In the above general Formulas Ia, Ib, and Ic, when Y and Y representalkylene, they can be straight or branched and when the group Y in thecompounds of Formula Ic is attached to a nitrogen atom of a heterocyclicgroup, is such that at least two carbon atoms separate the nitrogenatoms of the heterocyclic group and the guanidine group. The alkylenegroup Y thus stands,

1 inter alia, for methylene, 1,2-ethylene, Z-methylethylene,

1,3-propylene, 2-methy1-l,4-butylene, 1,6-hexylene; and the group Y thusstands, inter alia, for methylene,.1,2-

ethylene, 2-methylethylene, 1,3-propylene, 2-methyl-1,4-

butylene, and 1,5-pentylene.

In the above general Formulas Ia, b, or 0, when R R or R representbenzyl or in the compounds of Formula Ia, when R or R represent benzoyl,the benzene ring thereof can be unsubstituted or can bear one or moresubstituents of low molecular weight and of such nature that they do notinterfere with or take part in the reactions,

; sulfamoyl, and the like.

to be described hereinafter, used in the preparation of the compounds.Moreover, the nucleus of the group Ar in any of the compounds ofFormulas Ia, Ib, or Ic can also be further substituted in any of therings thereof by one or more of such substituents. Examples of suchsubstituents include halogen, lower-alkyl, lower-alkoxy,loweralkyl-mercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, nitro,trifiuo-romethyl, methylenedioxy, benzyloxy, benzyl, isonitrosomethyl,di-lower-alkylamino, lower-alkanoyl,

The compounds of Formula Ia where R R and R are hydrogen are prepared byreacting an aryl-nitrile or an arylalkanonitrile with hydroxylamine(suitably in the form of a hydrohalide salt) in an organic solvent inertunder the conditions of the reaction and in the presence of a base, forexample, alkali metal hydroxides, alkoxides, or carbonates. "A preferredbase is an alkali metal car bonate, for example, potassium carbonate orsodium carbonate. Suitable organic solvents are methanol, ethanol, 'is'opropan'ol, benzene, tolene, and the like. A preferred solvent isethanol. The reaction is represented by the equation: 4

direct alkylation of an aryl nucleus using anappropriatehalo-alkanonitrile. The alkylation can take place'either on aheterocyclic nitrogen atom bearing a replaceable hydrogen atom, or itcan take place on a carbon atom bearing an activated hydrogen atom. Theformer is illustrated by the preparation of a l-(cyano-alkyl)indolewhich is produced when indole (or a substituted-indole) is reacted witha halo-alkanonitrile in the presence of an acidacceptor. If alkylationof a ring carbon atom is desired, it may be necessary to carry out thealkylation indirectly, that is by reacting the halo-alkanonitrile with aGrignard reagent. This latter method is illustrated by the preparationof a 3-indolylalkanonitrile which is produced by reacting ahalo-alkanonitrile with a Grignard reagent formed from indole (or asubstituted indole) and a loweralkyl magnesium halide.

. A second method for the preparation of the arylalkanonitriles ofFormula II in which the alkylene group, Y, is Lil-ethylene comprisesreacting acrylonitrile with an aromatic compound having an activatedhydrogen atom either attached to a carbon atom or to a heterocyclicnitrogen atom. The reaction in the former case generally takes placespontaneously on admixture of the aromatic compound with theacrylonitrile, but in the latter case, it is generally necessary toemploy a strong base as catalyst, for example, potassium t-butoxide,sodium hydride, organo ammonium hydroxides, for example Triton B, andthe like.

The aryl-alkanonitriles of Formula II in which the alkylene group, Y, is1,2-ethylene can also be prepared by the catalytic reduction of thecorresponding 3-arylacrylnitrile. The latter in turn are prepared byreacting an appropriate aryl carboxaldehyde with cyanoacetic acid underbasic conditions and decarboxylating the resulting 3-ary1-2-cyanoacrylicacid over copper chromite.

Still another method for the preparation of the arylalkanonitriles ofFormula II where the alkylene group, Y, is methylene comprisesmetathetical replacement of a tertiary amino group of a Mannich basewith cyanide ion. This method is illustrated by the preparation of3-cyanomethyl-7-azaindole from 7-azagramine. The reaction is generallycarried out in an aqueous medium at the reflux temperature usingequimolar amounts of an alkali metal cyanide and a mineral acid. Apreferred reaction medium is aqueous dimethylformamide.

In some cases it is desirable to introduce the alkanonitrile side chainat the time of formation of the aromatic ring to which it is attached.Thus a cyanomethyl group is introduced at the 2-position of thebenzimidazole nucleus by reacting o-phenylenediamine with ethylcyanoacetate. The reaction is preferably carried out in the absence of asolvent.

The compounds of Formula Ia where R is lower-alkyl and R is hydrogen, orwhere both R and R are loweralkyl, are prepared by reacting a hydroxamicchloride derivative of Formula III below, wherein R Ar, Y, and n havethe meanings given hereinabove, with a loweralkylamine or adi-lower-alkylamine, R R NH. The com pounds of Formula Ia where R ishydroxy and R is hydrogen or lower-alkyl are prepared by reacting ahydroxamic chloride derivative of Formula III below, wherein Ar, Y, Rand n have the meanings given hereinabove, with hydroxylamine or anN-loWer-alkylhydroxylamine, R NHOH. These reactions are represented bythe following equations: 1

A preferred starting material of Formula III is one wherein R is benzyl.The products can then be debenzylated with hydrogen over a suitablecatalyst, for example, palladium-on-charcoal or Raney nickel, to producecompounds of Formula-Ia where R is hydrogen.

The arylhydroxamic chloride-O-benzyl ethers ar arylalkylhydroxamicchloride-O-benzyl ethers of Formula III (R is CH C H are prepared byreacting the corresponding arylamidoxime-O-benzyl ether oraryl-alkanoamidox- 'ime-O-benzyl ether of Formula Ia, where R and R areL l l NO CHgC H i, NO 01120 11 III (R3 is CHgCnHa) where Ar, Y, and nhave the meanings given above.

The arylhydroxamic chlorides or aryl-alkylhydroxamic chlorides ofFormula III (R is H) are prepared by the reaction of chlorine inchloroform with the corresponding aldoxime.

The compounds of Formula Ia where R;., is loweralkyl or benzyl areprepared by reacting the corresponding amidoxime, where R is hydrogen,with an alkali metal hydride in a suitable organic solvent inert underthe conditions of the reaction, for example, dimethylformamide, andreacting the resulting alkali metal salt with a loweralkyl halide or abenzyl halide. Alternatively, the alkali metal salt can be prepared byreacting the amidoxime with an alkali metal hydroxide in an aqueous oralcoholic medium, e.g. methanol, ethanol, or isopropanol. The reactionis represented by the equation:

/R /Ri Ar-YCN Ar-Y'CN L NOM R2 n L I IOR R n where R R R Ar, Y, and nhave the meanings given above, except that R is not hydroxy, and Mrepresents an ion of an alkali metal.

The compounds of Formula Ia where R is loweralkanoyl are prepared byreacting the corresponding amidoxime ethers, where R is lower-alkyl orbenzyl and R is hydrogen, with a lower-alkanoyl halide. When it isdesired to prepare the compounds of Formula Ia where R is lower-alkanoyland R is hydrogen, it is necessary to carry out the reaction with thelower-alkanoyl halide using the amidoxime O-benzyl ether (R is benzyl).Subsequent catalytic debenzylation affords the compounds where R ishydrogen.

The'com'pounds of Formula Ia where R is loweralkanoyl or benzoyl and Ris hydrogen or lower-alkyl are prepared by reacting the correspondingamidoxime with a lower-alkanoic anhydride or with benzoic anhydride, asthe case may be, in the presence of a base such as pyridine. Thereaction is preferably carried out in an excess of pyridine, as thesolvent medium, and at a temperature in the range from about C. to about50C.

, The compounds'of Formula Ia Where Y is a hydroxyalkylene group' 'withthe hydroxy group attached to the carbon atom adjacent to the amidoximegroup are prepared by reacting the corresponding cyanohydrin withhydroxylamine using the same conditions as described above for thepreparation of the compounds of Formula Ia where Y is a single bond oralkylene. The reaction is represented by the equation:

H NOH Ib where Ar, R Y, and n have the meanings given above and Alkrepresents lower-alkyl.

The compounds of Formula are prepared by reacting a 'lower-alkylisothiouronium halide with the corresponding arylalkylamine of FormulaIV below. The reaction is preferably carried out in an aqueous orlower-alkanol medium at the reflux temperature thereofJThe reaction isrepresented by the equation:

. Ic where Ar, R Y, and n have the meanings given above, and Alkrepresents lower-alkyl.

The aralkylamines of Formula IV are prepared by catalytic hydrogenationof the corresponding arylalkano nitr'iles of Formula II.

The novel compounds of the instant invention are the bases of FormulasIa, Ib, and la and the acid-addition salts of said bases. The compoundsof the invention in free base form are converted to the acid-additionsalt form by "interaction of the base with an acid. In like manner, thefree bases can be regenerated from the acidaddition salt form in theconventional manner, that is, bytreating the salts with strong aqueousbases, for ex ample alkali metal hydroxides, alkali metal carbonates andalkali metal bicarbonates. The bases thus regenerated can then beinteracted with the same or a different acid to give back the same or adifferent acid-addition salt. Thus the novel bases and all of theiracid-addition salts are readily interconvertible.

It will thus be appreciated that Formulas Ia, Ib, and Ic not onlyrepresent the structural configurations of the 'bases of my inventionbut each is also representative of the respective structural entitywhich is common to all of my respective compounds, whether in the formof the free bases or in the form of the acid-addition salts of thebases. I have found that by virtue of this common structural entity, thebases and their acid-addition salts have inherent pharmacodynamicactivity of a type to be more fully described hereinbelow. This inherentpharmacodynamic activity can be enjoyed in useful form forpharmaceutical purposes by employing the free bases themselves or theacid-addition salts formed from pharmaceutically-acceptable acids, thatis, acids whose anions are innocuous to the animal organism in effectivedoses of the salts so that beneficial properties inherent in the commonstructural entity represented by the free bases are not vitiated byside-effects ascribable to the anions.

In utilizing this pharmacodynamic activity of the salts of theinvention, I prefer of course to use pharmaceutically-acceptable salts.Although water-insolubility, high toxicity, or lack of crystallinecharacter may make some particular salt species unsuitable or lessdesirable for use as such in a given pharmaceutical application, thewaterinsoluble or toxic salts can he converted to the correspondingpharmaceutically-acceptable bases by decomposition of the salt withaqueous base as described above, or alternatively they can be convertedto any desired pharmaceutically-acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example by ion-exchangeprocedures.

Moreover, apart from their usefulness in pharmaceutical applications, mysalts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Like all of theacid-addition salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate thepharmaceuticallyacceptable free bases by reaction of the salts withaqueous base, or alternatively they can be converted topharmaceutically-acceptable acid-addition salts by, for example,ion-exchange procedures.

It will be appreciated from the foregoing that all of the acid-additionsalts of my new bases are useful and valuable compounds, regardless ofconsiderations of solubility, toxicity, physical form, and the like.

The novel feature of the compounds of the invention, then, resides inthe concept of the basesand cationic forms of the new amidoximes,amidines, and guanidines, and not in any particular acid anionassociated with the .salt forms of the compounds; rather, the acidanions,

which can be associated in the salt forms, are in themselves neithernovel nor critical andtherefore can be any acid anion or acid-likesubstance capable of salt formation with bases. In fact, in aqueoussolutions, the base form or water-soluble acid-addition salt form of thecompounds of the invention both possess a common protonated cation orammonium ion.

The acid-addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

Pharmacological evaluation of the compounds of Formulas Ia, Ib, and 10has demonstrated that they lower the blood pressure in dogs and ratsthus indicating their usefulness as hypotension agents. The compoundshave also been shown to possess psychromotor depressant, psychomotorstimulant, anti-inflammatory, and hexobarbital potentiation activitiesthus indicating their usefulness as tranquilizers, C.N.S. stimulants,anti-inflammatory agents and sedatives.

The compounds can be prepared for use !by dissolving under sterileconditions a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampoules for use by injection. Alternatively, they can be incorporatedin unit dosage form as tablets or capsules for oral administration or incombination with suitable adjuvants such as calcium carbonate, starch,lactose, talc, magnesium stearate, gum acacia, and the like. Stillfurther the compounds can be formulated for oral administration inaqueous alcohol, glycol, or oil solution or oil-water emulsions in thesame manner as conventional medicinal substances are prepared.

The chemical structures of the compounds of theinvention are establishedby their mode of synthesis and are corroborated by the correspondencebetween calculated values for the elements and values found by chemicalanalysis.

The following examples will further illustrate specific embodiments ofthe invention without the latter being limited thereto.

PREPARATION OF THE INTERMEDIATES Example 1(7-aza-1-indolyl)acetonitrile.[II: dolyl; Y is CH n is 1].

To a stirred solution of 5.9 g. (0.05 mole) of 7-azaindole in 50 ml. ofhot dimethylformamide was added 1.2 g. (0.05 mole) of sodium hydride inmineral oil. When hydrogen evolution had ceased, a solution of 3.77 g.(0.05 mole) of chloroacetonitrile in 5 ml. of dimethylformamide wasadded over a period of fifteen minutes. The reaction was stirred at roomtemperature for two hours, and taken to dryness in vacuo. The residuewas suspended in water and ether, extracted with a benzene/ ethylacetate mixture, and the combined organic extracts were taken todryness. Recrystallization of the residue from ether afforded 3.8 g. of(7-aza-1-ind0lyl)acetonitrile, M.P. 81.8-83.8" C. (corr.).

Examples 2-6 Ar is 7-aza-1-in- The following compounds of Formula II inTable 1 were prepared from an appropriate aromatic compound andchloroacetonitrile using the manipulative procedure described above inExample 1. The melting points are uncorrected unless noted otherwise.

[3 (2-cyanoethyl)-7-aza-1-indolyl] acetonitrile.[II: Ar is 1,3 (7azaindolyl); Y is CH (1 position) and (CH (3-position); n is 2].

A solution of 29.0 g. (0.17 mole) of fl-(3-indo1yl)- propionitrile in175 ml. of dimethylformamide was treated with 7.75 g. (0.32 mole) ofsodium hydride in mineral oil. When hydrogen evolutionhad ceased, themixture was treated with chloroacetonitrile and allowed to stand for twodays. The mixture was carefully decomposed with water, taken to drynessin vacuo, and the resulting oil suspended in water and extracted withether. The organic extracts were taken to dryness and the residueextracted with hot cyclohexane. The residue from the cyclohexaneextraction was dissolved in ether, washed once with aque: ous sodiumcarbonate, once with water, and the solution evaporated to dryness. Theresidue, on recrystallization once from benzene/ethanol and once fromethanol alone, afforded 9.02 g. of[3-(2-cyanoethyl)-7-aza-1-indolyl]acetonitrile, M.P. '106.5108.0 C.(uncorr.).

By following the manipulative procedure described above in Examples 1 or7, thefollowing aryl-alkanotriles of Formula II'where, in each case, nis 1' were prepared by reacting an aryl N het erocyclic compound with anappropriate haloalkanonitrile in the presence of sodium hydride: i pd-(3-chloro-1-indolyl) acetonitrile;

a- 3-.bromo-1-indolyl) acetonitrile;

u- 3-methyll-indolyl) propionitrile; (X-(7-I1'16thyl-1-ll'ldOly1)acetonitrile zx- (3-ethyl-1-indolyl) acetonitrile;u-(3-butyl-1-indolyl)acetonitrile, M.P. 42-3 C. (uncorr.)

(recrystallized from pentane); a-(2,5-dimethyl3-propyl-l-indolyl)acetonitrile, RR

130" C'./0.05 mm; I

a- 5 -m ethoxy- 1-indo1yl)acetonitrile;ot-(3-acetyl-1-indolyl)ace'tonitrile, M.P. 163-166" C.

(uncorr.) (recrystallized from ethanol); u(3-propionyl-lindolyl)acetonitrile, M.P. -115 C.

(uncorr.) (recrystallized from a tetrahydrofuranhexane mixture; n vu-(3-butyryl indolyl)acetonitrile, M.P. 84- -86 C.

(uncorr.) (recrystallized from an ethyl acetatehexane mixture);

96- 3-benzy1-1 -indolyl) acetonitrile;

' -[5-(10,1l dihydro-5H-dibenz[b,f]azepinyl)]butyronitrile, M.P.61.5-63.5 C. (uncorr.) (recrystallized from methanol);

ot-[9-(1,2,3,4-tetrahydrocarbazolyl) ]acetonitrile, M.P.

75 C. (uncorr.) (recrystallized from ethanol);a-[l-(lH-benzotriazolyl)]acetonitrile, M.P. 86.587.5 C.

(uncorr.) (recrystallized from benzene); and ot-[2-(2H-benzotriazolyl)]acetonitrile, M.P. 7279 C.

(uncorr.) recrystallized from ethanol).

Example 8 6-(3-ind0lyl)valeronitrile.[II: Ar is 3-indolyl; Y is (CH n is1].

A mixture-of 5.2 g. (0.215 mole) of magnesium turnings suspended inether 'was treated with a solution of 28.4 g. (0.20 mole) of methyliodide in ether. The resulting mixture was treated with a solution of23.4 g. (0.20 mole) of indole in ether, and the solution was refluxedfor about thirty minutes. The mixture was then cooled in an ice bath andtreated rapidly with'a solution of 32.4 g. (0.20 mole) ofa-bromovaleronitrile in ether. The mixture was stirred in an ice bathfor about two and one-half hours and then refluxed for eighteen hours.The mixture was then treated with aqueous ammonium chloride solution,and the organic layer was separated and washed three times with water,once with sodium bicarbonate, twice'again with water, and taken todryness giving 40.4 g. of a red-brown gum. Fractionation of the latterin vacuo and collection of the fraction boiling at 1l5l58 C./0.0003 mm.gave 14.9 g. ofcrude product which was recrystallized once fromethanol/penta'ne and once from ethyl acetate/hexane to give 10 g. of6-(3-indolyl)valeronitrile, M.P. 64.065.8 C. (corn).

I Examples 9-12 The following compounds of Formula II in Table 2 wereprepared from an appropriate indole and an appropriate wbromoallganonitrile using the manipulative procedure described above inExample 8. The melting points are uncorrected unless noted otherwise.

acetate/hexane. 1 13.1. 152.5 C./0.0007 111111. I 1 168169.5 0.;benzene. 1 132-1335 0.; benzene.

9 Example 13 6- (2-methyl-3-indolyl) propionitrile.[II Ar is 2-CH3-indolyl; Y is CH n is 1] was prepared from 39.36 g. (0.3 mole) ofZmethylindole, 31.85 g. (0.60 mole) of acrylonitrile, 0.25 g. of boricacid, and 0.7 g. of cu-pric acetate using the manipulative proceduredescribed above in Example 13. The crude material was purified bydistillation in vacuo, and the fraction boiling at 159167.0 C./0.25 mm.was collected as product. The latter was recrystallized from an ethylacetate/hexane mixture giving 29.6 g. of,6-(2-methyl-3-indolyl)propionitrile, M.P. 81-82 C. (uncorn).

Example fl-[2-methyl 1 (2-cyanoethyl) 3 indolyl]propionitrile.[II: Ar is2-CH -3-indolyl; Y is (CH (land 3-positions); n is 2].

To a slightly warm solution of 65.5 g. (0.50 mole) of 2-methylindole and0.5 g. of powdered potassium hydroxide in 65 ml. of t-butyl alcohol wasadded dropwise, over a period if forty-five minutes, 29.2 g. (0.55 mole)of acrylonitrile while maintaining the temperature below 55 C. Whenaddition was complete, the mixture was stirred for one half hour, thentreated with 1.0 ml. of glacial acetic acid, diluted with ether, washedwith water, and filtered to obtain 12.7 g. of crude product. The etherlayer from the filtrate was separated, taken to dryness, and theresidual oil distilled in vacuo up to 185 C./ 1.13 mm. The heel from thedistillation was triturated with methanol to give 5.05 g. of product.Recrystallization from ethyl acetate of the 12.7 g. crop of crudeproduct afforded an additional 4.50 g., thus giving a total yield of9.55 g. of fl-[2-methyl-1-(2-cyanoethyl)-3-indolyl]propionitrile, M.P.148.5-150.0 C. (uncorr.).

Example 16 about 1 g. of powdered potassium hydroxide in 125 ml.

of benzene was added 17 ml. of acrylonitrile. The mixture was stirredfor three hours, diluted with ethyl acetate, washed with water, and theorganic layer dried and taken to dryness giving 36.1 g. if a yellow oilwhich was distilled in vacuo. The fraction boiling at '101l02 C./ 0.08mm. was collected giving 33.1 g. of '{3-(7-aza-1-indolyl)propionitrile.The free base, dissolved in dry ether, was treated with hydrogenchloride in conventional manner giving ,8-(7-aza-1-indolyl)propionitrile in the form i of its hydrochloride salt, M.P. 151.0152.0C. (corr.).

By following the manipulative procedure described above in Examples13-16, the following fl-aryl-alkano nitriles of Formula II, where, ineach case, Y is (CH and n is 1 were prepared by reacting an arylN-hetero-' cyclic compound with acrylonitrile in the presence of a basiccatalyst:

/3-(3-ethyll-indolyl)propionitrile, B.P. 150 C./0.1 mm.;fl-(3-benzyl-1-indolyl)propionitrile, M.P. 83-85 C. (uncorr.)(recrystallized from ethanol); and

fi-(1-indolinyl)propionitrile, M.P. 115-117 C./0.3 mm.

Examples l722 The following compounds of Formula II in Table 3 wereprepared from an appropriate aromatic compound and acrylonitrile usingthe manipulative procedure described above in Example 16. The meltingpoints are uncorrected.

TABLE 3 Ex. Ar Y n M.P./Crystallizedfrom- 17 l-indolyl ongorn 1 B.P.150.3-152.o 040.94 1s- 2-CH -1-indolyl 01120112 1 842%18; ethyl acetate/$3333: i Fiiiiil dliaauy'rj 852% 1 $33 i'ililitaaa/ 21.-.-2-Cl-10-phenothiazinyl- CHZCHZ 1 18????8 0.; ethyl 22--..l-benzimidazolyl 01120112 1 103 1 32 0.

Example 23 ,B-(7-aza-3-indolyl)propionitrile.[II: Ar is 7-aza-3-indolyl;Y is (CH n is 1].

A solution of 44.5 g. (0.24 mole) of 3-dimethylaminomethyl-7-azaindole,36 g. (0.24 mole) of hexamethylenetetramine, and 190 ml. of 66%propionic acid was filtered and added, over a period of one hour, to arefluxing solution of 36 g. 0.24 mole) of hexamethylenetetramine in ml.of 66% propionic acid. The combined mixture was heated under reflux fortwo hours, diluted with 750 ml. of water, cooled, and after standing forthree hours, the solid which had separated was collected, washed withwater, and dried to give 17.2 g. of 7-aza-3-indolecarboxaldehyde, M.P.214217 C. (uncorr.).

The latter (0.118 mole) was dissolved in 600 ml. of ethanol along with11.0 g. (0.13 mole) of cyanoacetic acid and 13.7 g. (0.16 mole) ifpiperidine and refluxed for forty minutes. The reaction mixture wastaken to dryness, the residue dissolved in aqueous sodiumbicarbonate-sodium hydroxide solution, extracted with ether, andacidified to pH 6 with acetic acid. The solid which separated wascollected, washed with water, and dried giving 225 g. offl-(7-aza-3-indolyl)-a-cyanoacrylic acid, M.P. 250255 C. (uncorr.).

The latter (0.105 mile) was dissolved in 300 ml. of a eutectic mixtureof diphenyl and diphenyl oxide. One gram of copper chromite was added,and the mixture was heated under reflux for twenty minutes, filtered,cooled, and extracted with 1:3 hydrochloric acid. The acid extracts werewashed with ether, charcoaled, filtered, basified with aqueous sodiumhydroxide, and the solid which separated was collected and dried giving10.2 g. of crude product, M.P. 225-240 C. (uncorr.). Recrystallizationfrom acetonitrile afforded 5.1 g. of fl-(7-aza-3 indolyl) acrylonitrile,M.P. 246257 C. Further recrystallization from acetic acid/water gave1.93 g. of material having M.P. 256-259 C. (uncorr.).

The latter (0.011 mole) was suspended in ethanol and reduced withhydrogen over a palladium-on-charcoal catalyst, reduction being completein about twenty minutes. The reaction mixture was filtered, the solventremoved in vacuo, and the residue recrystallized twice from benzenegiving 1.14 g. of fi-(7-aza-3-indolyl)propionitrile, M.P. 170.0172.0 C.(corr.).

Example 24 The combined organic extracts were taken to dryness,

and the residual yellow solid recrystallized twice from benzene giving2.36 g. of ('4-chloro-3-indolyl)acetonitrile, M.P. 132.6-134.6 C.(corr.).

1 1 Example 25 Example 26 (7-aza 3 indolyl)acetonitrile.-[II: Ar is7-aza-3-indolyl; Y is CH n is 1] was prepared from 5.25 g. (0.03 mole)of 3-dimethylaminomethyl-7-azaindole, 7.38 g. (0.15 mole) of sodiumcyanide, 12.5 ml. (0.15 mole) of concentrated hydrochloric acid, and 750ml. of water using the manipulative procedure described above in Example25. The crude product was recrystallized from benzene giving 0.54 g. of(7-aza-3-indolyl)acetonitrile, M.P. 141.4142.6 C. (corn).

Example 27 (2-benzimidazolyl)acetonitrile.[II: Ar is 2-benzimidazolyl; Yis CH n is 1] A mixture of 25 g. (0.23 mole) of o-phenylenediamine and40 g. (0.35 mole) of ethyl cyanoacetate was heated at 180-183 C. forthirty minutes, cooled, washed with ether, and the ether-insolublematerial was collected and recrystallized from water giving 9.5 g. of(2-benzimidazolyl)acetonitrile, M.P. 206209 C. (uncorr.).

Example 28 3-cyano-7-azaindole.-[II: Ar is 7-aza-3-indolyl; Y is singlebond; n is 1]. 1

A mixture of 16.8 g. (0.115 mole) of 7-aza-3-indolecarboxaldehyde, 20.0g. (0.29 mole) of hydroxylamine hydrochloride, and 29.0 g. (0.29 mole)of sodium acetate trihydrate in 140 ml. of acetic acid was refluxed withstirring overnight, cooled, filtered, and the filtrate taken to dryness.The residue was slurried with water, filtered, and dried giving 11.8 g.of 3-cyano-7-azaindole, M.P. 249-252 C. (uncorr.).

Example 29 (l-methyl-7-aza-3-indolyl)acetonitrile.[II: Ar is 1- CH-7-aza-3-indolyl; Y is CH n is 1].

A suspension of 9.5 g. (0.21 mole) of sodium hydride 50 in 500 ml. ofdimethylformamide was treated with 31.4

g. (0.02 mole) of (7-aza-3-indolyl)acetonitrile. When hydrogen evolutionhad ceased, the mixture was treated with 13.1 ml. (0.2 mole) of methyliodide dissolved in a small amount of dimethylformamide over a period ofabout ten minutes. The reaction mixture was allowed to stand at roomtemperature for one week, diluted with 300 ml. of water and extractedwith ether. The combined extracts were taken to dryness and the residuerecrystallized from hexane giving 10 g. of(1-methyl-7-aza-3-indolyl)acet0nitrilc, M.P. 81-82.5 C. (uncorr.).

Example 30 (l-benzyl-7-aza 3 indolyl)acetonitrile.-[II: Ar is l- CgH CH-7-aza-3-indolyl; Y is CH n is 1] was prepared from 31.4 g. (0.20 mole)of (7-aza-3-indolyl)acetonitrile, 9.5 g. (0.21 mole) of sodium hydrideand 25.3 g. (0.20 mole) of benzyl chloride in 500 ml. ofdimethylformamide using the manipulative procedure described above inExample 29. The crude product was purified by chromatographing in etheron a column of 400 g. of activated magnesium silicate. The first literof eluate Was discarded, the second liter was taken to dryness, and theresidue from the latter recrystallized twice from benzene/ hexane giving14 g. of (1-benzyl-7-aza-3-indolyl)-aceto nitrile, M.P. 74.576 C.(uncorr.).

Example 31 4-chloro-2-cyanoindole.[II: Ar is 4-Cl-2-indolyl; Y is singlebond; 11 is 1] A mixture of 10.0 g. (0.052 mole) of 4-chloro-2-indolecarboxamide and 50 ml. of phosphorus oxychloride was heated under refluxfor thirty minutes until homogeneous, then cooled and poured into amixture of 400 g. of ice and 100 ml. of ammonium hydroxide. The mixturewas rendered basic by addition of more ammonium hydroxide, cooled, andthe solid which separated was collected and dried. Recrystallization ofthe crude product from benzene gave 5.3 g. of 4-chloro-2-cyanoindole,M.P. 167.4- 168.8 C. (corn).

In similar manner, a-(3-propyl-1-indolyl)acetonitrile was prepared .bydehydration of lx-(3-propyl-1-indolyl) acetamide with benzene sulfonylchloride and pyridine.

a-(3-dimethylaminomethyl 1 indolyl)acetonitrile was obtained as an oilby reaction of a-(1-indolyl)acetonitrile with dimethylamine andformaldehyde in acetic acid.

Examples 3260 By following one of the appropriate procedures given inExamples 1-31, using the appropriate starting materials, there can beobtained the compounds of Formula II listed below in Table 4, where n ineach case is '1.

TABLE 4 Example Ar Y 32 2-Br-5-(dibenzo[a,d][1,4]cycloheptadienylidenyl) (CHAS 33"- 6-F-2-indolyl (GHQ); 346-I-2-aza-1-indolyl h 35- 6-CF -2-aza-3indo1yl CH(CH 36".3-CH=NOH-4aza-l-indolyl H2); 37-.. 3-CH2N(CH )g-fi-azad-indolyl (CHM 38fi-aza-l-indolyl. OH(CH )CH2 39 4-aza-2-indolyl. CH 40...5-aza-2-indolyl. (CHM 4l 6-aza-2-indolyl. (CH2)2 42 7-aza-2-indo1yl-(01112) 43 4-aza-3-indolyl (GH 44... 5-aza-3-indolyl-.. (CHM 456-aza-3-indolyl- CH2); 46". 2-pyrroly1 CH (CH CH; 47 3-pyrroly CH2 48...l-pyrazolyl (CH2)2 49 3-pyrazolyl (CHZM 50 4-pyrazolyl (GHQ); 51...l-imidazolyL (GHQ); 52... 2-imidazolyL (GHQ). 53... 4-imidazoly1 CH2);54 G-CH;S-l-[lH-benzotrrazolyl] (CH2); 55 6-0H3S0-2-[2H-benzotriazoly1]H 56 3-CH S02-5-(10,11-dihydro-5H-dibenzo [b,f]az yl) -pyrrolyl -1-(pyrido-[2,1-e]s-triazolyl) (CH2) 3 13. Example 61 2-(2-methyl-7-aza 3indoly1)ethylamine dihydrochlon is 1].

Three grams (0.18 mole) of (2-methyl-7-aza-3-indolyl)- acetonitrile wereadded to about 125 ml. of absolute ethanol containing 15 ml. ofconcentrated hydrochloric acid. The mixture was reduced with hydrogenover 1.0 g. of platinum oxide catalyst at an initial pressure of 47pounds p.s.i., reduction being complete in about an hour. The catalystwas removed by filtration, the filtrate was taken to dryness in vacuo,and the residual solid was recrystallized from isopropyl alcohol giving35 g. of 2-(2-methyl-7-aza-3-indolyl)ethylamine dihydrochlorid M.P.286-309 C. (uncorr.).

Example 62 2-(7-aza-3-indolyl)ethylamine.[IV: Ar is 7-aza-3- Examples63-112 By following the manipulative procedure described above inExample 61, using an appropriate aryl-alkanonitrile, there can beobtained the compounds of Formula IV listed below in Table 5.

TABLE s Reduction of /3-(l-indolinyl)propionitrile with hydrogen over aplatinum oxide catalyst according to the procedure described above inExample 61 affords 2-(1- indolinyl)ethylamine [IV: Ar is l-indolinyl; Yis (CH n is 1].

PREPARATION OF FINAL PRODUCTS Example 113 B (7 aza3-indolyl)propionamidoxime dihydrochloride.[Ia: R R and R are H; Ar is7-aza-3-indolyl; Y is (CH nis 1].

A solution of 15.3 g. (0.09 mole) of ,B-(7-aza-3-indolyl) propionitrile,12.4 g. (0.170 mole) of hydroxylamine hydrochloride, 38 g. (0.36 mole)of anhydrous sodium carbonate and 1,500 ml. of ethanol was refluxed andstirred overnight. The hot mixture was filtered, the filtrate taken todryness, and the thick oily residue suspended in ethyl acetate, washedwith water and aqueous sodium chloride, dried, and taken to dryness. Theresidue was dissolved in absolute ethanol, the solution was acidifiedwith alcoholic hydrogen chloride and the solid, which separated oncooling, was collected, dried, and recrystallized from ethanol giving3.5 g. of fi-(7-aza-3-indolyl) propionamidoxime dihydrochloride, M.P.238.5239.0 C. (corn).

Examples 114-140 The following compounds of Formula Ia (R R and R are H)listed in Table 6 below were prepared from an appropriatearyl-alkanonitrile and hydroxylamine using the procedure described abovein Example 113. The melting points are corrected.

Example 63 64. 65 66 3-CH -1-indoly1 67 2-Ol-l0phenothiazinyl 68l-benzimidazolyl 2-CHa-7-aza-3-indolyl 7-aza-3-indolyl6-CF3-2-aza-3-ind0ly1 3-OH=NOH-4-aza-1-indolyl 3-OH2N(CH3)2-5-aza-1-indol 6-aza-l-indolyl 4-aza-2-indo1yl 5-aza-2-indolyl6-aza-2-indolyl 7-aza-2-indolyl 4-aza-3-indolylfi 6-CF3-2-benzimidazolyL1- pyrrolyl p 112 3-(pyrido-[2,1-c]-s-trizazolyl) (CHfi-F-l-benzimidazolyl.

2) 0 15 CH CH I. on om 2M OH(CH CHZCHZ Hi-H-Hl-I-H- HHHHHHHHHHHHHl-HHHHHHHHHHHHHHHHHHNHHlto r-n-HHM TABLE 6 Example Ar Y nM.P./crystallized from 2-CH3-Z-aza-3-indolyl" CH2 1 210.2-220.8 C.ethanol. 115-. 7-aza-3-gndolyl 1 175.4-1760 C. ethanol. 116-.7-aza-1-1ndolyl CH2 1 181.0181.6 C. ethanol. 117-. ..d (CH2)2 1129.5-1315 C. ethyl acetate. 118 1-CH3-7-aza-3-1ndolyl CH2 1 175.0185.0C. isopropanol/water. 119". 1-CaH5CHz-7'aza-3-1nd0lyl CH2 1 206.8207.0C. isopropanol/water. 120.. 1,3-(7-az a1ndolyl) CH2 2 203.0204.8 C.dimethylformamide/water. 121.. 7- aza'-3-1ndolyl CH2 1 162.0-163A C.water. 122-- 3-indolyl CH2 1 128.2134.0 C. ethyl acetate/hexane. 123+do" (CHz)z 1 169.8170.4 O. ethanol/ether. 124.- 2-CH -3-1ndolyl. (CHM 1175.2177.8 C. ethyl acetate. 125.. 5,6-O CHzO-3-1r idolyl CH2 1l83.8184.6 C. ethanol. 126-. 5,-d1-CH O-3-mdoly CH2 1 187.4188.0 C.ethanol. 127.. l-indolyl CH2 1 138.5-1395" C. ethanol/water. 128..3-CH3-1-1ndolyl. CH2 1 134.2135.6 C. ethyl acetate. 1 29.. l-lndolyl 1107.6111.6 C. ethyl acetate/hexane.

acH -lndolyl. 1 87.895.0 C. ethyl acetate/hexane. 3 CHg-l-lIldOly 1105.8107.2 C. benzene.

C H CH O-1 1 166.0167.6 C. ethyl acetate. 2-CH -1,3-mdolyl 2 184.0185.60. ethanol. 1,3indolyl l H 2 1524-1521 0. ethanol.

yrrolyl CH 1 90.0-91.6 0. benzene/hexane. 2-Cl-10-phenoth 1 147.8l49.0C. benzene. ...-dO CH2 1 1930-1941? 0. ethanol. l-benzlmidazolyl (CH2);1 182.8183.8 0. ethanol. 139 -do CH2 1 219.0219.5 0. ethanol. 1492-benz1midazolyl CH2 1 197.0199.0 C. ethanol.

Hydrochloride salt. +p-Toluenesulionate salt.

By following the manipulative procedure described above in Example 113,the following compounds of Formula Ia, where R R and R in each case isH, and n in each case is 1, were prepared by reacting the correspondingaryl-alkanonitrile with hydroxylamine:

a-(3-chloro-l-indolyl)acetamidoxime sulfate, M.P. 150.0-

151.0 C. (corr.) (recrystallized from an ethanol-ethyl acetate mixture);

a-(3-bromo-1-indolyl)acetamidoxime, M.P. 136.8l39.8 C. (corr.)(recrystallized from a tetrahydrofuran-ethyl acetate mixture);

00- 3-methyll-indolyl propionamidoxime hydrochloride,

M.P. 165.2-168.2 C. (corr.) (recrystallized from tetrahydrofuran andWashed with ether);

a-(7-methyl-1-indolyl)acetamidoxime sulfate, M.P. 151.6 153.0 C. (corr.)(recrystallized from an ethanol-ethyl acetate mixture);

a-(3-ethyl-1-indolyl)acetamicloxime hydrochloride, M.P. 158.0-159.0 C.(corr.) (recrystallized from ethyl acetate);

5 (3 ethyl-l-indolyl)propionarnid0xime sulfate, M.P. 178.0-178.6 C.(corr.) (recrystallized from an ethanol-isopropanol mixture);

a-(3-propyl-l-indolyl)acetamidoxime sulfate, M.P. 146.0-

148.0 C. (corr.) (recrystallized from isopropanol);

a-(3-butyl-1-indolyl)acetamidoxirne hydrochloride, M.P. 162.0-l64.0 C.(corr.) (recrystallized from ethyl acetate);

a-(2,5-dimethyl-3-propyl-l-indolyl)acetamidoxime, M.P. 140.0141.0 C.(corr.) (recrystallized from ethanol);

at (5 methoxy-l-indolyl)acetamidoxime, M.P. 150.0

l52.0 C. (corr.) (recrystallized from a tetrahydrofuran-hexane mixture);

zx-(3-acetyl-l-indolyl)acetamidoxime, M.P. 209.02l0.0 C. (corr.)(precipitated from dimethylformamide by dilution with water, collectedand washed with isopropanol);

a. (3 propionyl-l-indolyl)acetamidoxime, M.P. 208.0- 209.8 C. (corr.)(recrystallized from tetrahydrofuran);

a (3 butyryl 1 indolyl)acetamidoxime, M.P. 199.0- 199.6 C. (corr.)(recrystallized from tetrahydrofuran);

a-(3-benzyl-1-indolyl) acetamidoxime, M.P. 118.0-120.0 C. (corr)(recrystallized from an ether-hexane mixture);

fl-(3-benzyl-1-indolyl)propionamidoxime sulfate, M.P. 169.6-170.8 C.(corr.) (recrystallized from ethanol);

at (3 dimethylaminomethyl 1-indolyl)acetamidoxime, M.P. 148.2150.0 C.(corr.) (recrystallized from ethyl acetate);

,8-(l-indolinyl)propionamidoxime dihydrochloride, M.P. 177.4-182.0 C.(corr.) (recrystallized from ethanol); 7- [5 10,11 dihydro5H-dibe'nz[b,f]azepinyl)]butyramidoxime p-toluenesulfonate, M.P.187.8188.0 C. (corr.) (recrystallized from a methanol-ether mixture);oz-[9-(1,2,3 ,4-tetrahydrocarbazolyl ]acetamidoxime hydrochloride, M.P.168.0169.0 C. (corr.) (recrystallized from anethanol-tetrahydrofuran-ether mixture);a-[l-(lH-benzotriazolyl)]acetamidoxime, M.P. 207.6-

208.0 C. (corr.) (recrystallized from methanol anda-[2-(2H-benzotriazolyl)]acetamidoxime, M.P. 178.0-

179.0" C. (corr.) (recrystallized from ethyl acetate).

Example 141 (7 aza-3-indolyl)acetamidoxime O-acetate.[la: R and R are H;R is CH CO; Ar is 7-aza-3-indo1yl; Y is CH n is'l].

A solution of 19.0 g. (0.1 mole) of (7-aza-3-indolyl) acetamidoxime, 150ml. of pyridine, and 10 ml. of acetic anhydride was heated at 65 C. on awater bath for ten minutes, and taken to dryness in vacuo. Water wasadded to the reaction mixture, and again the mixture was taken todryness. The residue was slurried with water, filtered, dried, andrecrystallized from isopropanol giving 15 g. of(7-aza-3-indolyl)acetamidoxime O-acetate, M.P. 17 1.6172.6 C. (corr.).

By following the manipulative procedure described above in Example 141,the following compounds of Formula Ia, where in each case R and R are H,R is CH CO, Y is CH and n is 1, were prepared by reacting theappropriate a-(l-indolyl)acetamidoxime with acetic anhydride in thepresence of pyridine: a-( l-indolyl)acetamidoxirne O-acetate, M.P.118.0121.0

C. (corr.) (recrystallized from an ethyl acetate-hexane mixture); I a (3ethyl 1 indolyl)acetamidoxirne O-acetate, M.P.

149.0151.0 C. (corr.) (recrystallized from an ethyl acetate-hexanemixture); and

or (3 -,benzyl-l-indolyl)acetamidoxime O-acetate, M.P. 168.0169.6 C.(corr.) (recrystallized from an ethyl acetate-hexane mixture).

Example 142 7-aza-3-indolyl)acetamidoxime O benzoate-[Ia; R and R are H;R, is C H CO; Ar is 7-aza-3-indolyl; Y is CH n is 1].

T o a solution of 15 g. (0.08 mole) of (7-aza-3-indolyl) acetamidoximein ml. of pyridine was added, in small portions, 11.2 g. (0.08 mole) ofbeuzoyl chloride while maintaining the temperature below 35 C. Afterstanding Overnight, the solution was poured into 700 ml. of water 1 7and the gray precipitate that separated was collected, dried, andrecrystallized from ethanol giving 11.4 g. of (7-aza-3-indolyl)acetamidoxime O-benzoate, MP. 17 6.6-l78.4 C. (corr.).

By following the manipulative procedure described above in Example 142,the following compounds of Formula Ia, where in each case R and R arehydrogen, Y is CH and n is 1, were prepared by reacting the appropriatea-(1-indolyl)-acetamidoxime with an appropriate benzoylchloride in thepresence of pyridine:

By replacing the benzoyl chloride in the foregoing preparation byp-toluyl chloride, p-chlorobenzoyl chloride or S-methoxybenzoylchloride, there can be obtained the corresponding O-(p-toluate),O-(p-chlorobenzoate), or O-(3- methoxybenzoate), respectively, of(7-aza-3-indolyl)acetamidoxime.

Examples 143-176 By reacting an appropriate aryl-alkanonitrile withhydroxylamine using the manipulative procedure described above inExample 113, there can be obtained the compounds of Formula Ia (R R andR are H) listed below in Table 7, where n in each case is 1.

methylsulfonylbenzyl)ether, or O-( 4 trifiuoromethylbenzyl)ether, orO-(4-trifluoromethylbenzyl)ether.

Example 178 p (1 indolinyl)propionamidoxime O methyl ether. [Iaz R and Rare H; R is CH Ar is l-indolinyl; Y is (CH n is 1].

By reacting )9-(1 indolinyl)propionamidoxirne with methyl iodide in thepresence of sodium hydroxide, there can be obtained 3 (1-indolinyl)propionarnidoxime 0- methyl ether.

Example 179 /3-( l-indolinyl) N,N diethylpropionamidoxime.[Ia: R and Rare C H R is H; Ar is l-indolinyl; Y is (CH n is 1].

By reacting the B (1 indolinyl)propionamidoxime O- benzyl ether,described above in Example 177, with sodium nitrite in the presence ofhydrochloric acid at a temperature from about 0 C. to 5 C., there can beobtained fl-(l-indolinyl)propionohydroxamic chloride O-benzyl ether. Byreacting the latter with diethylamine, there can be obtained fi-(lindolinyl)-N,N-diethylpropionamidoxime O benzyl ether.

By reducing the latter with hydrogen over a palladiumon-charcoalcatalyst, there can be obtained ,B-(l-indolinyD-N,N-diethylpropionamidoxime.

Example 180 fi-(l indolinyl)propionohydroxamic acid oxime.-[Ia: R is OH;R and R are H; Ar is l-indolinyl; Y is (CH2)2; n is 1].

By reacting the [3-(-indolinyl)propionohydroxamic chloride O-benzylether described above in Example 179 with hydroxylamine, there can beobtained fl-(l-indolinyD-N- hydroxypropionamidoxime O-benzyl ether. Byreducing the latter with hydrogen over a palladium-on-charcoal cat TABLE7 Example Ar Y 143 2-BI'5-(di 144" 6F-2-indol 146.. 6-OF3-2-aza-3indolyl 147.. 3-CH=NOH-4-aza-l-indoly 148 3-CHQN(OH )g5-aza-1-indolyl149 fi aza-l-indolyl 150 4-aza-2-indoly1 156 6-aza-3-ind0lyl 157-.Z-pyrrolyL 158-. 3-pyr0lyl 159 l-pyrazoly 160.. 3 pyrazoly 161..4-pyraz0lyL.

162 l-imidazolyl 163 2-imidazolyl 164 4-irnidazolyl 165 6-CHS-l-[lH-benzotriazolyl] 168 G-F-l-benzimidazolyl 169."6-CF3-2-benzimidazo1yl 170 l-pyrrolyl 172 -ind0lyl 174" 2 CH3-3-indo1yl175 4-Cl-3-indo1y1 Example 177 i [i (1 indolinyl)propionamidoxime Obenzyl ether. [Iaz R and R are H; R is C H CH Ar is l-indolinyl; Y iS n.iS 1].

By reacting ;9-( l-indolinyl)propionarnidoxime with benzyl chloride,4-methylmercaptobenzyl chloride, 4-rnethylsulfonylbenzyl chloride, or4-trifluoromethylbenzyl chloride, in the presence of sodium hydroxide,there can be obtained, respectively, {3-(1-ind0linyl)propionamidoxime O-benzyl ether, 0 (4 methylmercaptobenzyl)ether, O (4- (CH2 3 CH(CH )CH22)z M (OH2)2 (CH2):

alyst, there can be obtained ;3-(1-indolinyl)-N-hydroxypropionamidoxime.

- Similarly, by replacing the hydroxylamine by N methylhydroxylamine,there can be obtained 3-( 1-indolinyl)-N-hydroxy-N-methylpropionamidoxime.

Example 181 }3( l-indolinyl -a-hydroxypropionamidoxime. [Ia: R R and Rare H; Ar is l-indolinyl; Y is CH CHQH; n is 19 By reactingowl-indolinyl)acetaldehyde with hydrogen cyanide, and reacting theresulting aldehyde cyanohydrin with hydroxylamine using the manipulativeprocedure de- 20 monia using the manipulative procedure described abovein Example 183, there can be obtained the compounds of Formular Iblisted below in Table 8.

TABLE 8 Example Ar I Y n 1 184 7-aza-1-ind0lyl CH 2 1851,3-(7-azaindolyl) CH2 1 186 1 lndolyl CH2 1 187 3-CH3'1-ind01yl OH; 1882-Ol-l0-phenothiazinyl CH 1 189 l-benzimidazolyL. CHgCH 1 1901,3-(7-azaondilyl) 2 191 2-CHs-3-indolyl (CHz)4 1 192 5,6OCH O-3-indolylCH 1 193 5,6-di-CH Q-3-indolyl CH2 1 194 2 CH3-1,3-indolyl (CH2): 2 1957-aza-1-indolyl (CH2) 2 1 196 2 CH3-1-indolyl- (CHQ l 197 3-CH3-1-indol(CH2); 1 198 -OsH CH O 1-1ndolyl (C 2)z 1 dolyl CH2 1 2CH3-7-aza-3-1ndolyl CH 1 7 aza 3-indol 1 1-CI"'3-78.Z3r3-i11d01 CH2 11-CuH5CH2-7-aza-3-indolyl CH2 1 204 4Cl-2-indolyl 1 2052-Br-5-(dibenzo[a,d][1,4142ycloheptadienylid 2): 1 206. 6-F-2-indoly1(CHfig 1 207.. 6-I-2 aza-1-indolyl (CHM 1 208.. 6-CF3-2-aza-3-indolCII(CH 1 209-. 3-CH=NOH 4-aza-1-indolyl. Hm I 210 3-OH N(CH3)-5-aza-1-indolyl m I 211 6aza-1-ind0lyl CH(CHa)C o l 212..4aza-2-indolyl CH 1 213 5-aza-2indol (CHQ 1 214 6-aza-2-indolyl (CHrgz 1215-. 7-aza-2-indolyl (CH 2 1 216-. 4aza-3-indolyl (CHM 1 2175-aza-3-indolyl 2)2 1 218.. 6-aza-8-indo1yl (011 l 219 2-pyrrolyl. OH(CH CH 1 220 3-pyrr0lyl (CHzlz l 221 l-pyrazolyl. (CHM 1 222.. e3-pyrazolyl CH 1 223 4-pyrazo1yl (01-12 1 224 l-imidazol (CHM 1 225 2)2'1 226.- (CI-I92 1 2)2 1 Y O m 1 229 3-CHSOp-5-(1O,1l-dihydro-fiH-dibenzo[b,f]azepinyl) (OHM 1 230fi-F-l-benzir'nidazolyl (CHM 1 23 6-0F -2-benzimidaz0lyl (CHzizl-pyrrolyl M 1 233 3-(pyrldo-[2,1-c]-s-triazolyl) (Cflzh 1 1 scribedabove in Example 113, there can be obtained fl-( l-indolinyl)-a-hydroxypropionamidoxime.

Example 182 B (1 indolinyl) N acetylpropionamidoxime O-acetate.[Ia: Rand R are CH O; R is H; Ar is l-indolinyl; Y is (CH n is 1].

By reacting fl-(l-indolinyl)propionamidoxime with acetic anhydride inthe presence ofpyridine, using the manipulative procedure describedabove in Example 141', there can be obtained;8-(l-indolinyl)-N-acetylpropionamidoxime O-acetate.

Example 183 (7-aza-3-indolyl)acetamidine hydrochloride.[lb: Ar is7-aza-3-indolyl; Y is CH n is 1].

Anhydrous hydrogen chloride was bubbled through a mixture of 3.1 g.(0.02 mole) of (7-aza-3-indolyl)aceto nitrile, 2.0 ml. of ethanol, and50 ml. of chloroform for about three hours while maintaining thetemperature around 0 C. and protecting the mixture from atmosphericmoisture. The mixture was taken to dryness in vacuo, and treated, whilecooling, with a solution of ml. of liquid ammonia in ethanol. The milkysuspension was then stirred at room temperature for three hours,filtered, and the filtrate charcoaled and taken to dryness. The residualgum was crystallized several times from ethanol giving 1.84 g. of(7-aza-3-indolyl)acetamidine hydrochloride, M.P. 254.0.-256.4 (3,(corn).

Examples 184-233 By treating an appropriate aryl=alkanonitrile withanhydrous ethanolic hydrogen chloride, followed by treatment Oftheresulting. imidate ester with alcoholic am= By reacting p-(l-indolinyl)propionitrile with anhydrous ethanolic hydrogen chloride,followed by treatment of the resulting imidate ester with alcoholicammonia or dime-thy-lamine using the procedure described above an EX-ample'183, there can be obtained, respectively, 8(1-indol-inyl)propionamidine [Ibt Ar is l-indolinyl; R is H; Y is (CH nis 1] or /8-(l-indolinyl) N,N-dimethylpropionarnidine (Ib: Ar isl-indolinyl; R is CH Y is (CH n is 1].

- Example 234 2 g (2 methyl 7 aza 3 indolyl)ethylguanidinehydrobromide.[Ic: Ar is 2-CH -7-aza-3-indo1y1; Y is n is 1].

A mixtureof 2.20 g. (0.013 mole) of 2-(2-methyl- 7-aza-3-indolyl)ethylamine and 3.47 g. (0.138 mole) of of ethylisothiouronium bromide (prepared from thiourea and ethyl bromide) in 7ml. of water was refluxed for six hours, cooled, taken to dryness, andthe residue recrystallized once from isopropyl alcohol and once frommethanol/ether giving 0.54 g. of 2-(2-methy1-7-aza-3-indo1yl)ethylguanid ine hydrobromide, M.P. 244.8-246.2 C. (corr.).

Example 235 2 (7 aza 3 indolyl)ethylguanidine hydrobromide.-[Ic: Ar is7-aza-3-ind0lyl; Y is (CH n is 1] was prepared from 15 g. (0.09 mole) of2-(7-aza3-i'ndolyl)ethy1'amine, and 25.8 g. (0.013 mole) of ethylisothiouorium bromide in ml. of water using the manipulative proceduredescribed above in Example 234. There was thus obtained 18 g. of crudeproduct which on recrystallization from methanol/ether gave 16.5 g. of2-(7-aza-3-indolyl)ethylguanidine hydrobromide, M.P. Z59.'62,6 1,Q 0. on),

21 By following the manipulative procedure described above in Examples234or 235, 7-aza-3-indoly1methylguanidine sulfate hydrate, M.P.256.6258.0 C. (corr.) (recrystallized from water) [Icz Ar is7-aza-3-indolyl; Y is CH n is 1] was prepared by reaction of 7-aza- 22sedative activity as shown by the potentiation of sleeping time inmice-induced by ether, thiopental sodium, or hexobarbital sodium. Theseactivities indicate their usefulness as hypotensive'agents,tranquilizers, and sedatives. 1

Hypotensive activity data are given for. representa-3-ifldolylmfithylamille With methyl isothiouronium 5 tive compounds ofFormula la in Table below where fateeach of the compounds is identifiedby the'number of the Examples 236-285 1 example above where itspreparation is described. The

By reacting an appropriate aryl-alkylamine with a low. activities areexpressed in terms of the AED, i.e. the Averer-alkyl isothiouroniumhalide using the manipulative pro- 10 age Effective Dose. As usedhereinafter, the abbreviations cedure described above in Example 234,there can be i.p., o, and s.c. designate intraperitoneal, peroral, andobtained the compounds of Formula Ic listed below in subcutaneousadministration, respectively. Table 9. 7

TABLE 9 Ar Y n Example: I

236 7-aza-1-indo1yl (CH2):

237 1,3- -azaindolyl) (CH2):

238 l-indolyl CH2)? 239 3-CH3-1-indol (OH2)2 240 2-Cl-10phen0thiazinylH2)2 241 l-benzimidazolyl 243 2-CHa-3-1ndol (CH-95 246 C z)s 2482'CHa1-indolyl (CH2) 3 249.- 3-CH;-1-indol (CH2);

282 6-F-1-benzimidazo1y1 283.. 6-C F -2-benzimidazolyl 284 s l-pyrrolyl285 3-(pyrido-[2,1-c]-striazolyl) M CH(CH3)CH2 2)4HHHHHHHHHHHHHHFHHb-H-H-H-H- HHHHHHHHHHHHP HHHHMHHH to r-n-n uzov-Example 286 3-[2-(1-indo1iny1)ethyl]guanidine. [Icz Ar is l-indolinyl; Ris H; Y is (CH n is 1].

By reacting 2-(1-indolinyl)ethylamine with ethyl isothiouronium bromide(prepared from thiourea and ethyl bromide) according to the proceduredescribed above in Example 234, there can be obtained 3-[2-(1-indolinyl)ethyl] guanidine.

Example 287 1,1 dimethyl-3-[2-(1-indolinyl)ethyl]guanidine.[Ic: Ar isl-indolinyl; R is CH Y is (CH n is 1].

By reacting 2-(1-ind0linyl)ethylamine with ethyl N,N-dimethylisothiouronium bromide (prepared from N,N-dimethylthiourea andethyl bromide) according to the procedure described above in Example234, there can be obtained 1,1-dimethyl-3-[2-( 1-indolinyl)ethyl]guanidine.

Pharmacological evaluation of the compounds of Formula Ia hasdemonstrated that they lower the blood pressure in rats and mice; theypossess psychomotor stimulant as Well as depressant activities asevidenced by studies in mice using standard activity cages; and theypossess HY-POTENSIVE ACTIVITY Table 10 Example: Activity, mg./kg. (s.c.)113 114 40 Psychomotor depressant activity data are given forrepresentative compounds of Formula Ia in Table 11 below. The activitiesare expressed in terms of the minimum effective dose (MED) and of thepercent decrease in motor activity.

Table 11 Example: Activity 119 MED=300 mg./kg. (p.o.); 55%. 121 MED=300mg./kg. (p.o.); 65%. 122 MED=300 mg./kg. (p.o.); 59%. 123 MED:100mg./kg. (p.o.); 61%. 133 MED=300 mg./kg. (p.o.); 78%.

Certain of the compounds also possess psychomotor stimulant activity inmice as evidenced by their ability to increase the motor activity ofmice in activity cages. Thus B-(S-benzyloxy 1 indolyl)propionamidoxime,described above in Example 132 was active at 12 mg./kg. (p'.o.),producing a 178% increase in motor activity.

Other compounds possess sedative activity as evidenced by their abilityto potentiate the sleeping time in mice induced by hexobarbital sodium.Thus the effective dose, ED ofB-(2-chloro-10-phenothiazinyl)propionamidoxime, described above inExample 136, in potentiating the sleeping time in mice to whichhexobarbital had been administered was found to be 45.5i8.7 mg./kg.(i.p.).

The compounds of Formula Ib have been found to possess hypotensiveactivity as determined in the renal hypertensive rat. Thus(7-aza-3-indolyl)acetamidine hydrochloride, described above in Example183, was found to have an Average Effective Dose, AED, of 8 mg./kg. whenadministered subcutaneously in the renal hypertensive rat.

The compounds of Formula Ic have also been found to possess hypotensiveactivity as determined in the renal hypertensive rat. Thus 2-(7-aza-3-indolyl)ethylguanidine hydrobromide, described above inExample 235, was found to have an Average Effective Dose, AED, of 30mg./kg. when administered subcutaneously in the renal hypertensive rat.

24 I claim: 1. A compound of the formula:

/R1 /R2 Ar-YFN or ArY-(FN L NOR; R2 L NR2 RQ (Ia) wherein:

Ar is: l-indolinyl; R is: hydrogen, lower-alkyl, lower-alkanoyl, orhydroxy; R is: hydrogen or lower-alkyl; R is: hydrogen, lower-alkanoyl,or lower-alkyl; Y is: a'single chemical bond or alkylene of from one tofive carbon atoms; and

n is: the integer 1.

2. A compound of Formula Ia according to claim 1 wherein R R and R arehydrogen; and Y is alkylene of from one to five carbon atoms.

3. p-(l-indolinyl)propionamidoxime according to claim 2 wherein Y is1,2-ethy1ene.

4. A compound of Formula Ib according to claim 1 wherein R is hydrogen;and Y is alkylene of from one to five carbon atoms.

References Cited UNITED STATES PATENTS 3,093,632 6/1963 Mull 260-2393,115,525 12/1963 DAlo 260-564 3,118,904 1/1964 Bolger 260-326.13,189,599 6/1965 Mull 260-239 3,189,601 6/1965 Mull 260-239 ALEX MAZEL,Primary Examiner J. A. NARCAVAGE, Assistant Examiner U.S. Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3 501.49? DatedMarch 17, 1 0

Inventor(s) Malcolm. R. Bell It is certified that error appears in theabove-identified potent i and that said Letters Patent are herebycorrected as shown below: I

ur- :i

* Column 1 line 1, 111 the title, "'(1-INDOLINYL)-LOWER 'AmLAmoximEs AND-AMIDINE" should read --INDOLINYL-LOWER- ALKYI AMIDOXIMES, -AMIDINES,AND -GUANIDINES-.-. Column 2, lines 17 and 18, "1-, 2-, and3-(6-1m1da'zoly1p'7 should read 7 --1-, 2-, and 3-(6-az a1ndolyl);--;line 18, after "3-(6- azaindolyl)" insert --l-, 2-, and3-(7-azalndolyl); 1- and g 2-benz1m1dazo1y1';-'---; line '25, that partor'tho structure" .1 showing '0 should show --c line .29, "here" shouldll r'qon NOR I E? reed "uhere"; 'line 31, "B B or'YR 7' should read "R Ror R line 34, "inter alia methyl ,ethyl'isopropyl or nbutyl-'-'-- shouldread "inter a11a,-met hl, ethyl, lsopropyl, or

n-buty1--. Column 3, line 5, "tolene should read "toluene- 11m 12, "Ar Yshould read --Ar, Y lines as and 47, "arylacrylnitrile" should read--arylaorylon1tr1le. Column t, line 15, that part of the equationshowing line- 22, "or" should read ---or--. Column 6 line 73,"hypotension" should read --hypotens1ve--; 11ne 7 4, :psychromotor"should read --ps chomotor--. Column 8, line 6,

alkanotriles" should read --a1 anon1t'r11es--. .Column 9, lines 35 and58, "11'" should read --ot--. Column 10, line 3, "11'" should read,--o,r--; line 43, "(0.105 mile)" shouldxfead --(o.1o5 mole). Columns l3and 14, Example 112, "tri-molyl" t read --1aoth1ouron1um- Zgygi UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTIQN Patent No- 3: 5 9? DatedMarch 17, 1970 Inventor(s) Malcolm H. Bell It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

:Ihould read --tr1'azo1yl--. Column 14, line 1 no (zu-tmmetho shouldshould read --0.l79 mole-F. Column 16 read 7-aza--. Column 17, line 9;

"0.170 mole" 1 "7-aza" should read 3 4 5-tr1methoxy--- Example 1'B-pyrol 1" ehouldread --3-pyrrolyI'L--. Column 18: line 33, lndolinylx"should read -(1-1ndol1ny1)--. Column 1 line 1, 'a- -1-1ndol1ny1) shouldread x-(l-lndol1mr1)--- Column 20, Ex le 190,- (T-azaondll 1--(7-ezaindo1yl --'-3 Example 211, CH

-- )CH Example 226, "(011 Example 229, "3- SO should read 3..

"an" should read "in"; lines 56 end 57 read ---of ethyl--;. and lines 69and 70','

line 47, "(31 0 3mm am SEALED m gom .should read w re a should read --QlC0--.

should reed 802-! line 5, or of ethyl" should

